According to the World health Organization, malignant tumours were responsible for 12 percent of the nearly 56 million deaths worldwide from all causes in the year 2000. In particular, 5.3 million men and 4.7 million women developed a malignant tumour and altogether 6.2 million died from the disease. The report also reveals that cancer has emerged as a major public health problem in developing countries, matching its effect in industrialized nations.
Although substantial progress has been made in the past two decades, there remain many cancers for which conventional therapy are either partially or totally ineffective. The main common problem with these therapies is unacceptable toxicity.
Thus, novel compounds, agents or methods are needed either to prevent the development of cancer, or, in the case where neoplasia has already developed, to render the host organism cancer-free or to reduce its neoplastic burden to a level compatible with life or at least to facilitate the use of concomitant therapies.
In its essence, neoplasia, including cancer, can be regarded as the inappropriate accumulation of cells, in violation of the delicate balance between cell renewal and cell death. For neoplasia to develop, either cell renewal must be increased or cell death decreased or both. A corollary to this relationship is that an agent that affects these processes favorably for the host organism (and, consequently, unfavorably for the neoplasm), is a potential antineoplastic drug.
Several antineoplastic agents have been isolated and identified from natural sources. For example, Curcumin (diferuloylmethane), a polyphenol derived from the plant Curcuma longa, commonly called turmeric has been extensively studied over the last 50 years and these studies indicate that this polyphenol can both prevent and treat cancer. More specifically, these series of studies have shown that Curcumin suppresses the proliferation of a wide variety of tumor cells, including breast carcinoma, colon carcinoma, acute myelogenous leukemia, basal cell carcinoma, melanoma and prostate carcinoma.(1-7) Despite the remarkable pharmacological safety profile of this compound, its effectiveness as a plausible anticancer agent has been limited by poor systemic absorption and extensive metabolism with administered doses.
A specific component of the honeybee hive product propolis, identified as caffeic acid phenyl ester (CAPE), has been shown to selectively inhibit the growth of viral-transformed and oncogene-transformed rodent cells as well as human tumor cells, including glioblastoma multiforme (GBM-18), colon adenocarcinoma (HT-29), and melanoma (HO-1) cells. These studies also show that CAPE and several additional caffeic acid esters inhibit azoxymethane-induced colonie preneoplastic lesions and ornithine decarboxylase, tyrosine protein kinase, and lipoxygenase activities associated with colon carcinogenesis.(8-13)
Although derived from different natural sources, CAPE and the Curcuminoids possess structural similarity that may likely explain their anticancer properties or at least partially explain their safety and selectivity profile. The significance of this structural similarity with regard to their anticancer properties is currently unknown.
An approach for developing new antineoplastic agents is to synthesize novel chemical compounds that are selective for cancer, stable in the biological milieu, maintain potency against cancer and exhibit low toxicity overall.
Banskota et al. (Journal of Ethnopharmacology (2002), 80(1), 67-73) isolated the cinnamic acid derivatives benzyl caffeate, phenethyl caffeate and cinnamyl caffeate, as well as the dicinnamate compounds (2E,2′E)-2-acetoxypropane-1,3-diyl bis(3-(4-hydroxyphenyl)acrylate) and (E)-2-acetoxy-3-(((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)propyl 3-(4-hydroxyphenyl)acrylate from a MeOH extract of Netherlands propolis. Benzyl caffeate, phenethyl caffeate and cinnamyl caffeate displayed EC50 values of 2.03 μM, 3.16 μM and 1.92 μM, respectively, against B16-BL6. The dicinnamate compounds (2E,2′E)-2-acetoxypropane-1,3-diyl bis(3-(4-hydroxyphenyl)acrylate) and (E)-2-acetoxy-3-(((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)propyl 3-(4-hydroxyphenyl)acrylate displayed moderate EC50 values of 81.9 μM and 66 μM, respectively, against the same cell line.